Parkinson disease (PD) is one of the most common neurodegenerative diseases. The histopathological hallmark of PD is neuronal degeneration in the substantia nigra, with Lewy body inclusions in many of the remaining neurons. Idiopathic PD is traditionally considered a disease of the extrapyramidal motor system, but there is growing realization that cognitive impairments are common in PD and often culminate in dementia, one of its most feared consequences: estimates of the cumulative incidence of dementia range from 38% to 65%, and prevalence as high as 78%. There are two main clinical diagnoses of dementia in PD: PD-dementia (PDD) and dementia with Lewy bodies (DLB). In PDD, motor signs and symptoms are the dominant features and dementia develops only after many years. In DLB, dementia occurs early, within one year of motor signs, and is often the initial and dominant feature. Although these clinical phenotypes are markedly different, the neuropathological findings in PDD and DLB are usually identical. By examining PDD and DLB patients early in their course of dementia, research proposed in this biomarker grant application will address this central question: Are these two forms of dementia variants of the same disease, or do they have different underlying processes? To resolve this question, we will examine three groups of patients - PD, PDD & DLB - with comprehensive neurological and neuropsychological assessments, and will perform innovative PET imaging using the dopamine transporter (DAT) ligand Altropane and the amyloid ligand PiB. The central hypothesis is that the extent and regional pattern of amyloid burden and mesolimbic dopamine impairment will distinguish DLB from PDD, and both from PD. This project draws upon the patient populations and rich research environment of the MGH/MIT Udall PD Center and the MGH Alzheimer's Disease Research Center. Successful completion of the project will establish DAT and PiB PET scans as potential biomarkers for dementia in the spectrum of Lewy body diseases. These advances will be important steps in devising improved treatments for dementia in Lewy body diseases. . Impaired thinking and dementia are disabling features of Parkinson disease that eventually affect 80% of patients. Successful completion of the proposed research will 1) define brain mechanisms that cause dementia, and 2) establish brain imaging methods to aid in the diagnosis of dementia in parkinsonian diseases. These advances will be important steps in devising improved treatments for mental impairments and dementia in Parkinson disease. [unreadable] [unreadable] [unreadable]